Upon induction of cyclooxygenase-2 (COX-2), neonatal ventricular myocytes (VMs) mainly synthesize prostaglandin E₂ (PGE₂). The biological effects of PGE₂ are mediated through four different G protein-coupled receptor (GPCR) subtypes (EP_1–4). We have previously shown that PGE₂ stimulates cAMP production and induces hypertrophy of VMs. Because the EP₄ receptor is coupled to adenylate cyclase and increases in cAMP, we hypothesized that PGE₂ induces hypertrophic growth of cardiac myocytes through a signaling cascade that involves EP₄-cAMP and activation of protein kinase A (PKA). To test this, we used primary cultures of VMs and measured [³H]leucine incorporation into total protein. An EP₄ antagonist was able to partially block PGE₂ induction of protein synthesis and prevent PGE₂-dependent increases in cell surface area and activity of the atrial natriuretic factor promoter, which are two other indicators of hypertrophic growth. Surprisingly, a PKA inhibitor had no effect. In other cell types, G protein-coupled receptor activation has been shown to transactivate the epidermal growth factor receptor (EGFR) and result in p42/44 mitogen-activated protein kinase (MAPK) activation and cell growth. Immunoprecipitation of myocyte lysates demonstrated that the EGFR was rapidly phosphorylated by PGE₂ in VMs, and the EP₄ antagonist blocked this. In addition, the selective EGFR inhibitor AG-1478 completely blocked PGE₂-induced protein synthesis. We also found that PGE₂ rapidly phosphorylated p42/44 MAPK, which was inhibited by the EP₄ antagonist and by AG-1478. Finally, the p42/44 MAPK inhibitor PD-98053 (25 μmol/l) blocked PGE₂-induced protein synthesis. Altogether, we believe these are the first data to suggest that PGE₂ induces protein synthesis in cardiac myocytes in part via activation of the EP₄ receptor and subsequent activation of p42/44 MAPK. Activation of p42/44 MAPK is independent of the common cAMP-PKA pathway and involves EP₄-dependent transactivation of EGFR.

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